The invention relates to an improved process for producing crystalline atorvastatin calcium which is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt.
Atorvastatin is useful as a selective and competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols such as cholesterol. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin as well as some of its metabolites are pharmacologically active in humans and are thus useful as a hypolipidemic and hypocholesterolemic agent. The liver is the primary site of action and the principal site of cholesterol synthesis. Clinical and pathological studies show that elevated plasma levels of total cholesterol and associated triglycerides promote human atherosclerosis and are risk factors for developing cardiovascular disease.
U.S. Pat. No. 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (xc2x1)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-xcex3, xcex4-dihydroxy-5-(1-methylethyl)-3-enyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
The above described atorvastatin compounds have been prepared by a superior convergent route disclosed in the following U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; and 5,149,837 which are herein incorporated by reference and Baumann K. L., Butler D. E., Deering C. F., et al, Tetrahedron Letters 1992;33:2283-2284.
One of the critical intermediates disclosed in U.S. Pat. No. 5,097,045 has also been produced using novel chemistry, as disclosed in U.S. Pat. No. 5,155,251 which is herein incorporated by reference and Brower P. L., Butler D. E., Deering C. F., et al, Tetrahedron Letters 1992;33:2279-2282.
U.S. Pat. Nos. 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,109,488; 5,969,156; U.S. Pat. No. 6,087,511; U.S. Pat. No. 5,998,663 and WO99/32434 which are herein incorporated by reference, disclose various processes and key intermediates for preparing atorvastatin.
Atorvastatin is prepared as its calcium salt, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-xcex3, xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration.
It was unexpectedly found that on scale-up to a commercial factory scale, the average crystal size of atorvastatin calcium was in some instances smaller than expected.
The object of the present invention is therefore to provide a process for producing crystalline atorvastatin calcium on a factory scale which routinely and consistently produces material in a consistent size range.
According to the invention there is provided a factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of:
(a) reacting a mixture of atorvastatin lactone, methanol, and methyl tert-butyl ether with sodium hydroxide to form the ring-opened sodium salt;
(b) forming a product rich aqueous layer and an organic layer comprising methyl tert-butyl ether containing impurities;
(c) removing the organic layer comprising methyl tert-butyl ether containing impurities;
(d) extracting the product rich aqueous layer with methyl tert-butyl ether;
(e) adding an extra charge of methyl tert-butyl ether to a vessel containing the product rich aqueous layer in an amount of at least 1% w/v of the contents of the vessel;
(f) sealing the reaction vessel;
(g) heating the contents of the sealed reaction vessel to 47xc2x0 C. to 57xc2x0 C. in the presence of the extra charge of methyl tert-butyl ether which saturates the the crystallization matrix on heating; and
(h) adding calcium acetate hemihydrate to the sealed reaction vessel to form atorvastatin trihydrate hemi calcium salt.
It was found that the addition of an extra charge of methyl tert-butyl ether after extractions with methyl tert-butyl ether ensures a saturated crystallzation matrix at the elevated temperature which has sufficient organic solvent content compensating for any increased solubility with heat and any loss to the headspace, and was surprisingly found to result in the formation of crystals of atorvastatin calcium within a consistent size range on a factory scale.
In a preferred embodiment of the invention the process includes the steps of:
preparing a mixed slurry in a pressurized slurry make-up/delivery vessel by:
(a) introducing water into the make-up/delivery vessel;
(b) introducing methanol into the make-up/delivery vessel;
(c) subsequently adding seed crystals of atorvastatin trihydrate hemi calcium salt to the make-up/delivery vessel; and
(d) after addition of calcium acetate hemihydrate to the vessel, adding the seed mixture thus formed from the pressurized make-up/delivery vessel to the sealed reaction vessel under pressure to maintain saturation of the crystallization matrix by methyl tert-butyl ether at the elevated temperature in the reaction vessel.
Preferably, the process includes the step of agitating the methanol and water in the make-up/delivery vessel to produce a solvent mixture before addition of the seed crystals to the make-up/delivery vessel.
In one embodiment of the invention the process includes the step of mixing the mixture of water, methanol, and seed crystals of atorvastatin trihydrate hemi calcium salt in the make-up/delivery vessel to form a seed crystal slurry for delivery from the pressurised slurry make-up/delivery vessel into the sealed pressurized reaction vessel containing the heated crystallization matrix saturated with methyl tert-butyl ether.
In a preferred embodiment the make-up/delivery vessel is pivotally mounted on a support frame and the methanol and water mixture are agitated by rocking the make-up/delivery vessel to produce the solvent mixture.
In a particularly preferred embodiment the make-up/delivery vessel is pivotally mounted on a support frame, and the solvent mixture and seed crystals are mixed by rocking the make-up/delivery vessel to form the seed crystal slurry.
The invention also provides a process which allows a seed slurry of atorvastatin to be prepared quickly and efficiently, and which can be introduced to the reaction vessel under pressure thereby maintaining a sealed system. A sealed system is maintained throughout the atorvastatin calcium crystallization process to prevent the loss of solvents to evaporation.
In one embodiment of the invention delivery of the seed slurry from the pressurised make-up/delivery vessel into the sealed pressurized reaction vessel is commenced not more than 5 minutes after commencement of the addition of calcium acetate.